Clinical trials are a critical component in the development of new medicines. However, they are also highly complex and require careful planning and execution. Manufacturing of clinical trial materials (CTMs)—products used in clinical studies—is one of the key challenges when designing and executing the trials.

This article explores the importance of CTM manufacturing and outlines how flexible, on-demand processes can improve clinical trial efficiency.

Treatments for rare diseases and evidence-based medicine

In recent years, there has been an increased interest in treatments for rare diseases across development pipelines. This has influenced the growing focus on clinical trials. Rare diseases, which affect smaller patient populations, have historically been overlooked by the industry due to the perception that their treatments are not commercially viable. However, advances in medical research have expanded our understanding of diseases and their underlying mechanisms, leading to the development of many new treatment options and therapies.

Clinical trials play a crucial role in evaluating the safety and efficacy of these innovative therapies before they can be widely applied in practice. Among healthcare professionals and patients, there is also a growing emphasis on evidence-based medicine, which relies on high-quality research and clinical evidence to guide medical decisions. Clinical trials provide the necessary data to assess the benefits and risks of new treatments, helping medical professionals and their patients make informed treatment choices. Patient advocacy is also important, and clinical trials provide an opportunity for patients to access new therapies before they become widely available, giving them hope for improved outcomes.

The rise of personalized treatments

The concept of personalized medicine, which tailors treatments to individual patients based on their genetic, environmental, and lifestyle backgrounds has gained prominence in recent years, too. Clinical trials help to identify biomarkers and subpopulations that may respond differently to certain treatments, enabling the development of targeted therapies. Crucially, there is now an industry-wide recognition of the importance of collaboration and data sharing in medical research. Clinical trials facilitate the sharing of knowledge, data, and best practices. This leads to more efficient and effective development of treatments, meaning that therapeutics for smaller patient populations are more viable than ever before and are a more attractive target for industry focus.

Simultaneously, the focus on virtual, hybrid and decentralized models is transforming clinical trials. This is particularly advantageous considering the volume of clinical trials currently ongoing: as of May 8, 2023, there are approximately 451,538 registered clinical trials.¹

In combination, these trends are greatly influencing the shift away from traditional manufacturing to more flexible processes accommodating new trial models and smaller batch sizes.

CTM manufacturing and the importance of getting it right

CTMs are the materials that are used in clinical trials, such as investigational, placebo or comparator drug studies. The manufacturing of these materials is crucial to the success of the clinical trial, as any variation in the composition or quality of the CTM can impact the accuracy of the trial results. There are a few key considerations that must be kept in mind when manufacturing CTMs:

1. Ensuring patient safety. Patient safety is the primary concern throughout clinical trials. CTM manufacturing must follow strict quality control procedures to ensure that the investigational product is manufactured correctly as errors could compromise patient safety. Therefore, the manufacturing of CTMs is highly regulated, and there are strict guidelines that must be followed to ensure that the materials are safe and effective. This includes following good manufacturing practices (GMP) and adhering to regulatory requirements set by the FDA, EMA, and other regulatory bodies. Failure to comply with these can lead to delays in approvals or even rejection of the trial. This would result in significant financial costs for the developer.
2. Availability of materials. In addition to regulatory compliance, CTM manufacturing also requires careful planning and coordination to ensure that the materials are available when needed for the clinical trial. This includes forecasting the required quantities of the CTM, estimating the timelines for manufacturing, and ensuring that the materials are delivered to the clinical trial sites on time.
3. Confidence in quality. The goal of a clinical trial is to assess the efficacy of the investigational product. If the CTM manufacturing process is flawed or inconsistent, it can introduce variability into the product’s composition, making it difficult to accurately evaluate its effectiveness. By ensuring appropriate CTM manufacturing processes, researchers can have confidence in the quality and consistency of the investigational product being tested.
4. Scalability options. In addition, CTM manufacturing is often a precursor to larger-scale production if the investigational product proves to be safe and effective. Ensuring that the manufacturing process is scalable and reproducible from small-scale production to larger batches is essential for future commercialization and widespread availability of the product. Efficient and effective CTM manufacturing can help optimize costs and resources associated with clinical trials. By minimizing errors and maximizing production efficiency, resources can be utilized more effectively, reducing costs, and minimizing waste.

Strategies to consider for CTM manufacturing

Fundamentally, when considering options for CTM manufacturing, the key consideration is meeting the needs of the clinical study. This is often overlooked at the point of formulation and product design, with final distribution and patient needs missed due to the emphasis on product stability.

There are three potential strategies that should be considered when deciding on product manufacturing options:

1. Traditional bulk manufacture. Traditional bulk manufacturing involves large upfront-scale manufacture of the final product, whether that is a tablet, capsule or otherwise. This is typically performed by a contract development and manufacturing organization (CDMO) who then ships the product to the clinical research organization (CRO). Each CRO site will hold seeded stock either for dispensing in the clinic or to be sent directly to the patient.
2. Bright-stock manufacture. Bright-stock manufacturing is a viable option when looking for more flexibility in supply. As with traditional bulk manufacturing, this CTM manufacturing method involves large bulk manufacture upfront by the CDMO or at a secondary location. However, following production, products for clinical use are held in final containment without labeling. When the end product is identified as needed, it is then labeled and distributed to clinical sites for on-site clinical use or shipment to patient homes.
3. Personalized real-time manufacture. When working with challenging patient populations, personalized real-time manufacturing of CTMs is a good option. Focusing on small batches, this form of manufacturing involves only producing the CTM at the point it is known to be required. It will then be immediately packaged, labeled, and distributed.

Flexible, on-demand product manufacturing

Traditionally, CTMs are manufactured in large bulk batches. This is suitable for large-scale clinical trials and reduces the number of batches and analytical testing required, but bulk manufacturing can lead to inefficiencies and waste if not all the materials are used in the clinical trial. Additionally, traditional CTM manufacturing can be inflexible, making it difficult to adjust the production schedule if there are changes in the clinical trial timeline or if additional materials are needed.

Bright-stock manufacturing could be a suitable alternative, offering more efficient use of stock since products are held in final containment and not labeled until required. However, although bright-stock manufacturing offers some flexibility, there are still some restrictions. The CTM product is still packaged, so there is no flexibility in varied doses or providing additional units for clinical trials.

To improve clinical trial efficiency and address the challenges found with bulk batch manufacturing, flexible, on-demand product manufacturing is a solution. Personalized real-time manufacturing allows for the efficient and cost-effective production of CTMs. This approach involves the manufacture of CTMs in smaller batches, on an as-needed basis, using a flexible manufacturing platform.

The benefits of on-demand CTM manufacturing

On-demand CTM manufacturing allows for a patient-focused approach to clinical trials. It also offers several benefits, including:

1. Reduced waste. On-demand manufacturing allows for the precise production of the required amount of CTMs, reducing the amount of waste associated with traditional batch manufacturing. It also reduces the risk of excess CTMs becoming obsolete due to protocol amendments, trial terminations or changes in patient enrollments. As a result, resources are utilized efficiently, and waste-associated costs are largely reduced.
2. Increased flexibility. On-demand manufacturing is highly flexible, allowing for adjustments to the manufacturing schedule based on changes in the clinical trial timeline or the need for additional materials. Flexible manufacturing supports adaptive trial designs, where protocols can be modified. This approach would allow for adjustments in CTM production to align with protocol changes such as dose escalation or de-escalation. Enhanced trial flexibility reduces study delays and enables quicker decision-making in the clinic.
3. Improved efficiency. On-demand manufacturing eliminates the need for large-scale production runs and reduces the time required for product release, compared with traditional batch manufacturing.
4. Cost-effectiveness. By reducing lead times and minimizing waste, flexible, on-demand manufacturing can contribute to cost-effectiveness in clinical trials. Efficient utilization of resources and reduced product losses will result in significant cost savings for investors, ultimately making trials more affordable and sustainable. This will open trials to larger patient demographics.
5. Promoting a patient-focused approach. On-demand manufacturing enhances a patient-focused approach to clinical trials by minimizing the risk of supply shortages, delays, or interruptions, therefore improving the patient experience. This in turn may increase patient adherence and retention in the trial.

Moving forward: flexible, on-demand manufacturing strategy

The CTM supply chain is complex, and it is important to consider all its aspects. It is essential to ensure that the product is in the right format and is delivered to the right place at the right time. The needs of the patient should always be at the forefront. The CTM manufacturing strategy should allow for the timely and reliable availability of the investigational product to trial participants.

When creating a CTM manufacturing strategy, it is crucial to consider product type and CTM design, remembering that there is no right or wrong way to strategize getting your product to the trial centers.

The most cost-effective and time-effective consideration would be to approach CTM manufacturing on a per-trial basis, with clinical supply, product integrity through distribution and the needs of the patient all determined per-trial.

Following the decision on the type of CTM manufacturing, there are other important considerations around potentially outsourcing to an experienced company. It is important to carefully assess all aspects of the supply chain involved in CTM manufacturing to ensure the product is of the highest quality. The best strategy toward CTM manufacturing would be:

• Working with a manufacturer with a thorough understanding of the supply chain. This means that there will be consideration of sourcing raw materials, manufacturing processes, packaging, labeling, storage, transportation, and distribution—during planning. Each step should be carefully evaluated to identify areas for improvement.
• Considering a tailored approach. There is no one-size-fits-all strategy when it comes to CTM manufacturing. Each product type and clinical trial design may have unique considerations. Working alongside a manufacturing company that will evaluate various strategies to determine the most appropriate approach for your specific circumstances is likely the most cost-effective option.
• Effective management of clinical supplies throughout the trial. It is essential to maintain some form of clinical supply management. This includes forecasting demand, managing inventory, and coordinating resupply. Having robust systems in place to track and manage this is vital to prevent a shortage of supplies and wastage, both of which will cost funds and time.

By carefully evaluating these factors, a company can make informed decisions about CTM manufacturing.

Future thoughts

CTM manufacturing is a critical component in the development of new medicines, and getting it right is essential for the success of the clinical trial. Flexible, on-demand product manufacturing is a solution to the challenges associated with traditional CTM manufacturing, offering increased flexibility, improved efficiency, and reduced waste. By leveraging this approach and working with a CDMO that offers the ideal approach to CTM, clinical trial sponsors can improve their chances of success and bring new medicines to patients faster.

References
1. https://clinicaltrials.gov/ct2/resources/trends

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Nick McEntee has over 25 years’ experience in drug product manufacturing and clinical trial supplies distribution within the pharmaceutical industry and has experience in development, manufacture, and global distribution of a wide range of dosage forms. He has a broad experience across the CDMO sector covering a range of related disciplines including GMP manufacturing, clinical trial supplies management, process and capability development, cleanroom build, and pharmaceutical equipment qualification and validation. In his current role with Quotient Sciences Nick works closely with clients to assist with scoping their clinical trial distribution needs ensuring drug products are manufactured, packaged, and labelled to maximize efficiency and flexibility while ensuring both clients and ultimately patients’ needs are met through the early phase development program up to proof of concept.